Dr Warner Huh (Host): Hello, everyone. Again, this is Dr. Warner Huh, the Chair of Obstetric and Gynecology here at the University of Alabama at Birmingham. And I want to welcome you to this monthly episode with Women's Health with Dr. Huh. So, I have an outside guest speaking with me today. And I want to welcome Dr. Gretchen Wells in a second. But we're going to talk about cardiac health and hormone replacement therapy, what our patients really need to know.

And with me today is Dr. Gretchen Wells. Actually, Dr. Wells is a Birmingham native and a nationally recognized leader in Clinical Cardiology. She did her education, both got her MD and PhD here at UAB and then went off to complete her residency and fellowship in Cardiovascular Diseases at Wake Forest School of Medicine in Winston-Salem, North Carolina.

Since that time, her career has really skyrocketed and she's really held numerous leadership roles, including the Director of Inpatient Cardiology and was the Associate Dean for Missions at Wake Forest and was also the Director of the Women's Heart Health Program at the University of Kentucky Gill Heart and Vascular Institute, where she was the first and inaugural Thomas Whayne Endowed Professor in Women's Heart Health within the American College of Cardiology.

She was also the co-investigator for the Women's Health Initiative, which we're going to talk about shortly and why that's important for this podcast, has led numerous, numerous, cardiology-based clinical trials. She has a litany of awards she's received over her career, including being recognized as one of the best doctors in America for many, many years, and was also the recipient of the American Heart Association Council on Clinical Cardiology, Women in Cardiology Mentoring Award. So, Dr. Wells, welcome to the podcast today.

Dr Gretchen Wells: Thank you, Dr. Huh. It's a pleasure to be here and looking forward to discussing hormone therapy in postmenopausal women.

Host: So, just as a preamble, you know, you and I had an earlier conversation, about my interest in this topic. I'm at that age and my wife is at the day certainly where heart health and being menopausal is a reality. And I have learned that some of this is sort of misunderstood, or poorly understood, not just in the medical community, but the general community. And so, one of the things I want to try to accomplish today is sort of right-sizing and getting our listeners to better understand what that risk of heart disease is in women, particularly as it relates to the use or non-use of hormone replacement therapy. So very briefly, I had done a prior podcast with Bill Hurd, who's one of our professors in Reproductive Endocrinology in the department. And we talk about really what are the real risks and benefits of , and what we know is much based on the Women's Health Initiative or WHI.

And what I'll argue is that I think that the results from that study, A, have been misunderstood and misapplied to women in general. And I know that's something you and I see eye to eye on. So, before we go into the questions related to cardiac risk in women and how to risk mitigate, can you just talk a little bit about what is the Women's Health Initiative, or WHI, and what were the initial conclusions from this really very large study?

Dr Gretchen Wells: The Women's Health Initiative was conceived really by Dr. Bernadine Healy in the early 1990s when she had assumed the directorship of the National Institutes of Health. She proposed that chronic diseases and prevention of chronic diseases be studied in women. At that time, no study of this kind had been undertaken.

The budget for the Women's Health Initiative was approved by Congress in 1992 and enrollment began in 1993 to 1998. Again, this was a very large study of postmenopausal women, ages 50 to 79. And in total, there were 161,808 women who wound up in this study. The study itself consisted of three clinical trials initially, one of which was hormone therapy, and an observational study. Many of the patients wanted to be in one of the clinical trials, but for one reason or another could not be, or chose not to be, so they were enrolled in an observational study in order to determine risk factors, natural history, and so on.

Host: So, can you just comment on what were the primary objectives of the study in certain terms of when they executed it? What did they really want to look at as their primary endpoints?

Dr Gretchen Wells: The primary endpoints vary for each clinical trial. For the hormone therapy trial, the primary endpoint was a reduction in coronary heart disease. The primary safety outcome, of course, had to do with breast cancer, and any estrogen-sensitive cancer and the secondary outcome were hip fractures. There were two other clinical trials, some of which overlapped this partial factorial design, and those were a low-fat diet and a calcium and vitamin D supplementation. The low-fat diet coronary heart disease was a secondary outcome.

Host: And can you comment on what the results were from the cardiovascular primary endpoint?

Dr Gretchen Wells: In the hormone therapy trial, I prefer to think of it as two separate trials. There was an estrogen and progestin trial and an estrogen-only trial. The women who had an intact uterus took the estrogen plus progestin, because we know that estrogen alone would increase the risk of endometrial cancer. So, there were roughly about 17,000 women in the estrogen and progestin trial and roughly about 10,000 women in the estrogen-only trial.

Initially, all seemed to be going well, their lipid panels improved, insulin levels go down, and so on after the first year. However, a couple of years into the study, there appeared to be an increased risk of clotting events such as stroke, blood clots in the lungs, and so on, and participants were told of this concern. And then, finally, in the spring of 2002, the Data and Safety Monitoring Board recommended that the study be terminated due to an increased risk of stroke, blood clots in the lung, as well as breast cancer. Now, this is in the estrogen and progestin-only study, and not achieving the primary outcome of a reduction in coronary heart disease, which was characterized by heart attacks. There was not a reduction in heart attacks. So, the study ended early, but they continued to follow these women.

The estrogen-only trial continued for another year or so. And once again, they did not find a significant reduction in coronary heart disease. However, there was a marked increased risk in stroke and blood clots to the lung, as well as what we call a global index, which characterized heart disease, strokes, cancers, death, and so on.

Host: I'm going to briefly get into the breast cancer issue, because I think it's important for us to kind of recapitulate that. So, we talk about, in clinical trials and epidemiology, this general concept of generalizability. And so, when we do clinical trials, our listeners may not understand that we're sometimes looking at sometimes a fairly narrow set of patients that meet certain criteria. And it's really kind of scientifically inappropriate to say that group X applies to group Y. So, how do we take that information? And obviously, I would argue that WHI had an older cohort of women by age, but we have women who are perimenopausal who are younger that are using HRT. Do we throw the baby out with the bath water here? So, in other words, I mean, can we really state that there is no cardio-protective or benefit effect with HRT, particularly in younger women?

Dr Gretchen Wells: You bring up an excellent point, Dr. Huh, and thank you for asking that question. Here is the catch with the Women's Health Initiative. The average age of enrollment was 63. The average age of menopause in the United States is 51. So, as a scientist, you would even ask, who knows what happens to these receptors, these estrogen receptors, in the absence of ligand all these years? But we're looking at clinical trial data here. And what we are seeing is that in young people, there actually did appear to be some benefit, it just was not statistically significant at a reduction of coronary heart disease. And if you put the participants in three buckets, those ages 50 to 59, those ages 60 to 69, and those ages 70 to 79, the problems were not seen in those in the younger age group, 50 to 59 and 60 to 69, where we really start to see the problems were those in ages 70 to 79.

Host: I think that point is really important, and I'll use the breast cancer example as a good point of this, the thing that I remember distinctly when I was finishing my residency, I was going into fellowship, and it seemed like everyone at that time was on a hormone replacement drug called Premarin.And then, all of a sudden, WHI came out with those results, and all of a sudden everyone came off Premarin. And for about, I would say at least 15 years, if not longer, we inadvertently withheld HRT from, I would argue, millions of women, right? And the three things that you mentioned about WHI, which are the three things I worry about, are breast cancer, cardiovascular disease, and hip or spine fracture. And I think that it speaks to, unfortunately, two things. One, and I hope I don't go off the rails too much saying this, is that it speaks to some of the scientific illiteracy that, unfortunately, the press has, but also some of the scientific illiteracy that maybe we have, as the medical field, and this concept of absolute risk and relative risk. You know, people hear, "Oh, there's a 20% increased risk of breast cancer," but when you put that contextually in terms of the actual number of cases that are occurring, it's a really, really small, almost arguably an infinitesimal number. And I think we've scared a lot of people, including physicians and providers, away from that. And I think we've done the same thing as with perhaps cardiovascular disease and risk mitigation. I don't know how you feel about that, but it's something that I've grown to really appreciate as I go down that rabbit hole and understand this data better.

Dr Gretchen Wells: I agree with you regarding the breast cancer. And in fact, the numbers from the Women's Health Initiative were the risk change absolute from one in 5,000 to one in 4,000. So again, that's important to know the difference between absolute risk reduction and relative risk reduction. It was still very small.

The other point regarding not as many Premarin or Prempro prescriptions being written is that hormone therapy was and still is FDA approved for the treatment of perimenopausal symptoms. The WHI did not address that. The question addressed in WHI was "Does hormone therapy decrease the risk of coronary heart disease in postmenopausal women?" Taking them together as a group, ages 50 to 79, the answer was no, meaning the primary outcome of a 20% risk reduction was not achieved.

Host: We could spend so much time on this. And it gets hard, because I want to make sure that our listeners who are the general public kind of understand the more salient points of this discussion, but that's the reason you're here, so we could talk about this. Let's talk a little bit contextually about cardiac risk and events in women over the course of their lifetime. I know you feel this, but I've always learned that the presentation, particularly of symptoms, are different in women than it is in men. But maybe you could just briefly explain to the audience about just what their risk is, the events that happen in women, and how that changes over the course of the lifetime. I know we've talked about perimenopausal, postmenopausal, premenopausal, but it might be interesting for women to hear what that risk looks like over the course of their lifespan.

Dr Gretchen Wells: Over the course of their lifespan, approximately one in three women are going to die of cardiovascular disease. What we know is that most of this can be prevented, and these are very simple tools for prevention.

Host: And we'll just jump right into there. What does that prevention look like from you as an esteemed cardiologist? What do you tell your patients in terms of how do they mitigate their risk?

Dr Gretchen Wells: Very simply, don't smoke. You need to quit. You know you should quit. Maintain a healthy blood pressure, 130/80 or less is the current recommendation. Eat a healthy diet, preferably one that is primarily plant-based. If you have type 2 diabetes, appropriate treatment. Cholesterol levels, it depends on what your overall risk is and there are some great tools available on the internet to help you determine whether or not you should be on a statin. Most of these tools for risk mitigation are easily available on the internet. There are some other risks that this audience may need to pay attention to. For example, an early menopause, that is associated with an increased cardiovascular risk. We're hearing more now regarding pregnancy complications that women have earlier in life that may contribute to a cardiovascular risk later.

Host: So, just so I understand this correctly, as you mentioned, the average age of menopause in the US is 51. but there are a substantial number of women who go through what we call premature ovarian failure, they may stop producing estrogen in their late 30s and 40s. And so, what I'm hearing from you is that perhaps those women need to think about earlier rather than later about these modifications in their diet, their behavior, but also do you think that they should be formally evaluated for their risk? I think this is such an untapped area. I don't know if really OB-GYNs in general think about it this way, but I think that they should. Just as an example, should they get plugged in with a cardiologist or what should they think about with their OB-GYN or their PCP, their primary care person?

Dr Gretchen Wells: Absolutely. They need to have their risk addressed early, because we know that earlier treatment will mitigate later risk of an actual event.

Host: And just going back to the original topic of the podcast, which was around cardiac disease and HRT, so, as it stands today, which is why I think very few of us have used Premarin or Prempro anymore, right? There are tons of other formulations, not just pills, patches, you know, et cetera. How do we address the relationship between cardiac risk and modern day HRT? It's an area that's somewhat data free at this point, but I also want to be very careful that we not necessarily repeat the same mistakes and base it on the WHI, which I understand what the cardiac risk, but I think that world is different. I just don't know if you have any professional opinions about how we address that question with women.

Dr Gretchen Wells: I believe that question should be addressed on an individual basis between a woman and her physician. There clearly are some women who should not be on hormone therapy, particularly those who have estrogen sensitive cancers, those who smoke, those who have untreated clotting disorders, and so on. However, to throw hormone therapy completely out for all women is a serious mistake.

Host: And I was remiss and I'm glad you added the whole issue related to vasomotor symptoms, because that and vaginal atrophy and dryness are number one and number two of the complaints that women have and not that the other issues aren't important. But I agree with you. I mean, it's got to be done on an individual level, but I just would like for us to start thinking about cardiac disease on the same playing field level as cervical cancer screening. So, every woman in the United States knows when they get their annual exam, they probably get a Pap. Whether that's right or wrong, that's a different podcast, right? But they should be thinking about what their cardiac risk is. And it's like the opportune time to have that conversation. I mean, the one in three statistics that you mentioned is just so darn striking to me that I just don't think that we have put our heads around that and really understood how to assess, and how to mitigate that risk. And we have the tools. You all in the Cardiology world have made such incredible progress whether it's with drug development, diagnostics, understanding genetic implications of disease that I just feel so strongly that we got to pass on the gospel related to this area, basically.

Dr Gretchen Wells: Thank you. And I agree with you, Dr. Huh, regarding that statement. I tell patients all the time, "You know your shoe size, you know your bra size, tell me what your cholesterol is, tell me what your blood pressure is, tell me what your hemoglobin A1c is." And they may not know. But through conversations such as this, I believe that we're raising awareness as to how important this really is, because this can be treated and heart disease can be prevented.

Host: You and I talked about this earlier and I think we're going to do a separate podcast on just cardiac events in women, whether pregnant women, postpartum women, postmenopausal women. But one of the things that you share with me, which I have to remind myself, is that when a woman has a cardiac event, their clinical presentation is very different than a man's, right? And so, as a man, we all are at the general public here, if you have chest pain, you get pain radiating to your neck or your arm. But can you just share with me what you shared in terms of how the presentation is different in women? Because I think this captive audience should hear this. This is actually really, really important, because it's not a one-size-fits-all.

Dr Gretchen Wells: That is correct. It can be chest pain. It can be the left arm numbness, dizziness, shortness of breath, and so on. It can also be indigestion. It can also be fatigue. When something is not right, this needs to be investigated. And I am so glad that you brought up pregnant women. Pregnant women can and do have heart attacks. And a common cause is a spontaneous coronary artery dissection. And we have seen those here, we have seen those across the country. Many times, these women are ignored because they are so young, they believe that they can't be having a heart attack. They don't present to the emergency room as they should. And even providers will think, "Oh, she's too young." They need to get an EKG, they need to get their enzymes, because this could be a life threatening problem that we're just now beginning to understand.

Host: That's going to be the tee up to the next podcast. And I think we have one of the preeminent places that does research in the area of hypertension, heart disease, particularly in pregnancy with individuals like Alan Tita and Rachel Sinkey. So, in the near future, we're going to talk about that, because I think that's definitely under-discussed and under-appreciated for sure. Anything that you want to share with the audience and the listeners before we close out the podcast today, Dr. Wells?

Dr Gretchen Wells: Keep at it. Let's keep having these discussions. Hormone therapy is safe in the appropriate patient. We should not condemn it because the trial was misinterpreted when the findings of the trial were hormone therapy should not be initiated in the postmenopausal woman for the prevention of coronary heart disease. That was the take-home point. It was never meant to stop hormone therapy altogether. And unfortunately, it was misinterpreted and that is what has happened.

Host: Absolutely. And that's been the takeaway point on this podcast as well as the last one I did with Dr. Hurd, is just kind of setting the record straight. And I think we've got a lot of work to do. But I think one thing that we appreciate is really, truly understanding this risk-benefit quality of life ratio that is so important. So, I do think the needle is swinging in the other direction. But I think we still have a long way to go. So, I think how we prescribe HRT to women is so much more sort of open-minded and balanced than it was 10, 15 years ago. But like most things in life, things moved glacially and slowly. But hopefully, we'll continue to spread the message like you said, and create awareness not just with our providers, but also with our patients as well.

So anyway, well, thank you again, Dr. Wells, for discussing this topic. It's really immensely important. I can think you can tell I'm in this as a cancer surgeon. It's a little bit odd I would be interested in this, but some of it hits home for me personally, but also I think it's important for the women that we serve.

So, as always, please rate this podcast and we welcome any comments, particularly in topics that you all have been interested in. And for more information on heart health, heart disease and women's services at UAB or other clinical services, please check out uabmedicine.org. Until next time, thank you. Have a great day. Summer's upon us, and we'll see you next month. Take care. Peace out. Bye-bye.